Etidronate prevents dystrophic cardiac calcification by inhibiting macrophage aggregation

Sci Rep. 2018 Apr 11;8(1):5812. doi: 10.1038/s41598-018-24228-y.


Cardiovascular calcification is associated with high risk of vascular disease. This involves macrophage infiltration of injured vascular tissue and osteoclast-related processes. Splenic monocytes from mice, that are predisposed (C3H) or resistant (B6) to calcification, were isolated and differentiated in vitro with M-CSF to generate macrophages, which aggregate to form multinucleated (MN) cells in the presence of RANKL. MN cell formation was significantly decreased in monocytes from resistant compared with calcifying mice. Conditioned media from C3H macrophages strongly induced calcification in vitro. However, medium from B6 macrophages inhibited calcification. An increase in ICAM-1 was detected in conditioned media from C3H macrophages compared with B6, suggesting a key role for this molecule in calcification processes. Due to natural genetic loss of Abcc6, the causal gene for cardiac calcification, C3H mice have reduced plasma levels of inorganic pyrophosphate (PPi), a potential calcification inhibitor. Supplementation of C3H mice with PPi or Etidronate prevented but did not completely reverse cardiac calcification. Our data provide strong evidence of the pathogenesis of macrophages and MNs during tissue calcification and suggest PPi or its analogue Etidronate as a potential inhibitor of MN formation and calcification. Furthermore, the adhesion molecule ICAM-1 was shown to play a key role in calcification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Density Conservation Agents / administration & dosage*
  • Calcinosis / prevention & control*
  • Cardiovascular Diseases / prevention & control*
  • Cell Aggregation / drug effects*
  • Cells, Cultured
  • Diphosphates / administration & dosage
  • Etidronic Acid / administration & dosage*
  • Intercellular Adhesion Molecule-1 / analysis
  • Macrophages / drug effects*
  • Mice, Inbred C3H
  • Mice, Inbred C57BL


  • Bone Density Conservation Agents
  • Diphosphates
  • Intercellular Adhesion Molecule-1
  • Etidronic Acid